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Published online before print January 24, 2003, 10.1148/radiol.2263011737
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(Radiology 2003;226:691-697.)
© RSNA, 2003

Ultrasonography

Coarse Nodular US Pattern in Hepatic Cirrhosis: Risk for Hepatocellular Carcinoma1

Eugenio Caturelli, MD, Luigi Castellano, MD, Saverio Fusilli, BSc, Bruno Palmentieri, MD, Grazia A. Niro, MD, Camillo del Vecchio-Blanco, MD, Angelo Andriulli, MD and Ilario de Sio, MD

1 From the Department of Anatomy and Histopathology, Gastroenterology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy (E.C., S.F., G.A.N., A.A.); and Department of Internal Medicine and Gastroenterology, II Università, Naples, Italy (L.C., B.P., C.d.V.B., I.d.S.). Received October 24, 2001; revision requested January 14, 2002; final revision received July 8; accepted July 31. Address correspondence to E.C., Gastroenterology Unit, Ospedale Belcolle, Strada Sammartinese, 01100 Viterbo, Italy (e-mail: e.caturelli@tiscalinet.it).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine the prevalence of the coarse nodular ultrasonographic (US) pattern and its prognostic importance in terms of hepatocellular carcinoma (HCC) risk in hepatic cirrhosis caused by hepatitis B virus (HBV); HBV with hepatitis D virus (HDV), formerly known as hepatitis delta virus; hepatitis C virus (HCV); and alcoholic cirrhosis (ALC) or primary biliary disease (primary biliary cirrhosis [PBC]).

MATERIALS AND METHODS: Four hundred two cases of hepatic cirrhosis caused by HBV (94 patients), HDV (100 patients), HCV (100 patients), ALC (63 patients), or PBC (45 patients) were retrospectively reviewed to identify the US pattern present at diagnosis and its possible association with the cause of the disease and subsequent development of HCC during a mean follow-up of 43.9 months ± 29.9 (SD). Data were analyzed with the {chi}2, Fisher exact, and log-rank tests and with the Kaplan-Meier method (all two-tailed).

RESULTS: The coarse nodular pattern was found in a significantly higher percentage of patients with HDV-related cirrhosis (51%) compared with those with HBV (9%), HCV (9%), ALC (11%), or PBC (9%) (P < .001). This pattern was associated with a significantly increased risk for HCC in patients with cirrhosis and HBV-, HCV-, and ALC-related disease but not in those with HDV-related disease and PBC.

CONCLUSION: The coarse nodular pattern is more often seen in patients with HDV-related cirrhosis, and, in this setting (in contrast to HBV-, HCV-, and ALC-related cirrhosis, as well as in PBC), it does not represent an added risk factor for HCC.

© RSNA, 2003

Index terms: Liver, cirrhosis, 761.794 • Liver, US, 761.1298 • Liver neoplasms, 761.323


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Ultrasonographic (US) diagnosis of liver cirrhosis is characterized by high specificity, ranging from 79.9% to 100%, and sensitivity, ranging from 43% to 87.7% (1–3). The most widely accepted signs of this disease are an increased ratio of the size of the caudate lobe to the right lobe (1,4); superficial nodularity (3,5), which is best detected with high-frequency probes (2,6); and a coarse parenchymal echo pattern (7). In some patients with cirrhosis (or chronic hepatitis), the latter finding is accompanied by the presence of small (3–6-mm in greatest dimension) hypoechoic nodules scattered throughout the liver tissue (8). Although these nodules share some of the US features of hepatocellular carcinoma (HCC), they generally contain no neoplastic cells. Nonetheless, the "coarse nodular pattern" is believed to represent an additional risk factor for HCC development, particularly in patients with hepatitis C virus (HCV)–related cirrhosis (9). There is little or no information in the literature, however, about the prognostic significance of this parenchymal echo pattern in other etiologic groups of cirrhosis.

Since its identification, hepatitis D virus (HDV), formerly known as hepatitis delta virus, has been detected in a subgroup of patients with chronic liver disease related to the hepatitis B virus (HBV). Our experience over the past 15 years indicates that the coarse nodular pattern is particularly common in patients with cirrhosis related to this type of combined infection. This observation prompted us to conduct a retrospective study of patients with different causes of hepatic cirrhosis to determine the prevalence of the coarse nodular US pattern and its prognostic significance (in terms of HCC risk) in each subgroup regarding the cause.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients
The protocol for this retrospective study was approved by the medical ethics committees of the centers that took part in the study. Informed consent for review of patients’ records and images was not a prerequisite for approval and was not obtained.

The study involved 402 cases of hepatic cirrhosis that had been diagnosed between January 1, 1985, and December 31, 1999, in our two centers. In 402 cases, the definitive diagnosis of cirrhosis was based on histologic findings in 81 (20.1%) cases; on upper endoscopic findings (ie, esophageal varices and/or congestive gastropathy) and laboratory abnormalities (ie, prolonged prothrombin time, decreased platelet count and serum albumin and cholesterol levels, and increased total bilirubin and gamma globulin levels) in 46 (11.4%) cases; US findings and laboratory abnormalities in 244 (60.7%) cases; and clinical presentation (ie, cutaneous spider angiomas, abdominal subcutaneous portosystemic shunts, and mild ascites) and laboratory value abnormalities in the remaining 31 (7.7%) cases.

At the time of diagnosis, the cirrhosis was considered to be compensated (ie, no evidence of jaundice, severe ascites, hepatic encephalopathy, or severely impaired coagulation) in all cases, and the patients’ Child-Pugh scores ranged from class A5 to B7. None of the patients included in the study had experienced bleeding from esophageal varices prior to diagnosis, and none had any signs of HCC at the time of diagnosis or in the 3 months following diagnosis.

The patients were categorized into five subgroups that were described on the basis of the cause of the patient’s liver disease. These subgroups were as follows: HDV group, 100 patients who had HDV- with HBV-related cirrhosis; HBV group, 94 patients who had cirrhosis related to HBV alone; HCV group, 100 patients with cirrhosis caused by HCV infection; alcoholic cirrhosis [ALC] group, 63 patients with alcohol-related cirrhosis; and primary biliary cirrhosis (PBC) group, 45 patients with PBC (Table 1). Apart from the HDV group, no attempt was made to include subgroups of patients in whom more than one etiologic factor (eg, combined HBV and HCV infection or viral hepatitis with alcohol abuse) could be identified or those with rarer etiologic forms (eg, secondary to autoimmune disease or hemochromatosis), because such groups would have been numerically inadequate for statistical analysis.


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  		TABLE 1. Characteristics of Etiologic Subgroups of Patients with Cirrhosis in the Study

 
Retrospective Classification of Hepatic Parenchymal US Patterns
Each patient considered in the study underwent abdominal US at the time cirrhosis was diagnosed. US was performed with three real-time scanners as follows: One unit (SSA 250-A; Toshiba, Tokyo, Japan) equipped with a 3.75-MHz convex probe was used from 1985 through 1996 in one center and from 1985 to 1994 in the second center. A second unit (Tosbee; Toshiba) equipped with a 3.75-MHz convex probe was used from 1995 through 1999 at the second center, and a third unit (Eccocee; Toshiba) equipped with a multifrequency (3.5–6.0-MHz) convex probe was used from 1997 to 1999 at the first center. The images had been recorded on instant film.

During the retrospective analysis, the recorded images from each scan were independently evaluated by two reviewers (E.C., G.A.N., L.C., B.P.), with one pair at each center, who were blinded to the cause of the cirrhosis and all other clinical characteristics of the case. Both reviewers were experienced in hepatic US, and in most cases, they had performed the original US examinations and interpreted the findings.

On the basis of the findings at the retrospective analysis of the reviewers, the hepatic parenchymal echo patterns were classified as follows: (a) normal homogeneous pattern (Fig 1); (b) bright liver pattern, characterized by the presence of numerous, fine, tightly packed echoes of high signal intensity uniformly distributed throughout the liver parenchyma (10) (Fig 2); (c) coarse pattern, represented by the presence of nonhomogeneous, coarse, thick, uneven echo spots without any distinct hypoechoic nodules (10) (Fig 3); and (d) coarse nodular pattern, in which multiple weakly hypoechoic nodules (<6 mm in diameter) were scattered diffusely over a background displaying the coarse echo pattern previously described (9) (Fig 4). The final classification represented concordant independent judgments or, when discordant opinions were expressed by the two reviewers, consensus decisions that were based on joint review of the recorded images.



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  		Figure 1. Oblique US scan of the right subcostal area of the liver. Normal homogeneous pattern is observed in a patient with PBC.

 


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  		Figure 2. Oblique US scan of the right subcostal area of the liver. Typical bright liver pattern characterized by the presence of numerous, fine, tightly packed echoes of high signal intensity uniformly distributed throughout the liver parenchyma is observed in a patient with HBV-related cirrhosis.

 


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  		Figure 3. Oblique US scan of the right intercostal area of the liver. Typical coarse echo pattern with nonhomogeneous, thick, uneven echo spots without any distinct hypoechoic nodules is observed in a patient with HCV-related cirrhosis.

 


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  		Figure 4. Oblique US scan of the right intercostal area of the liver. Typical coarse nodular pattern with multiple small (<6-mm) weakly hypoechoic nodules (arrowheads) scattered over background pattern of coarse echoes is observed in a patient with HBV- and HDV-related cirrhosis.

 
Follow-up and Diagnosis of HCC
All of the patients included in the study had also undergone follow-up examinations (ie, clinical evaluation, routine blood chemistry tests including serum AFP, and abdominal US) at 4–6-month intervals. The follow-up US examinations had been performed in the manner described previously by the same examiners (E.C., G.A.N., L.C., B.P.) who had performed the original scanning. In those patients in whom coarse nodular patterns were manifested when the cirrhosis was first diagnosed, each follow-up scan had been carefully assessed by the original examiners for possible variations in the shape and/or dimensions of the small hypoechoic nodules that characterized this pattern. When the scan revealed one or more focal liver lesions with well-defined borders and diameters larger than 1 cm accompanied by serum AFP levels greater than 200 ng/mL (200 µg/L), the patient was considered to have HCC and was scheduled for treatment. Patients with all other focal lesions depicted at follow-up US underwent US-guided fine-needle biopsy, contrast material–enhanced computed tomography (CT), or hepatic angiography to determine a definitive diagnosis.

The retrospective analysis was limited to follow-up data obtained through December 31, 2000, and a minimum follow-up period of 12 months was available for each of the patients considered. These data were examined by two of the authors (A.A., I.d.S.) who were not involved in the retrospective classification of the original US patterns. For each of the five subgroups, the number of cases in which HCC had been diagnosed was recorded during follow-up. These cases were diagnosed on the basis of US findings; diagnostic AFP levels; and biopsy, CT, or hepatic angiographic findings. The outcomes used for the analysis (ie, HCC or no HCC) were based exclusively on follow-up data in the patients’ charts, that is, no attempt was made to review follow-up US images to determine if they contained evidence suggestive of HCC that had been missed by the original examiners.

Statistical Analysis
Statistical analyses were performed with a software package (BMDP; Statistical Software, Los Angeles, Calif). The mean ± SD was used for descriptive analysis of continuous data. The inferential analysis was performed with the {chi}2 test, and the Fisher exact probability test was used for categorized data. The Kaplan-Meier method was used to estimate the risks of HCC associated with the coarse echo pattern and the coarse nodular pattern. The log-rank test was used to estimate the probability of cumulative risk of HCC associated with the coarse echo pattern and the coarse nodular pattern. All tests used were two tailed, and a P value of .05 or less was considered to represent the minimal level of a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Parenchymal Echo Patterns at the Time of Diagnosis
Table 2 shows the hepatic parenchymal US patterns identified by the reviewers on the initial scans obtained at the time of diagnosis in each of the etiologic subgroups. The final classification represented concordant independent judgments in 389 (96.8%) of 402 cases; in the remaining 13 cases, discordant opinions were expressed by the two examiners, and the final classification was based on findings at joint review of the recorded images. The cases in which discordant judgments were initially expressed were uniformly distributed throughout the 15-year study period and appeared to show no association with the scanner or type of transducer used.


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  		TABLE 2. Classification of Hepatic Parenchymal Patterns Observed at US at Diagnosis of Cirrhosis

 
Table 2 shows that there is a statistically significant (P < .001) association between the US pattern present at diagnosis and the cause of hepatic cirrhosis. The coarse nodular pattern was found in 51 (51%) of 100 patients in the HDV Group. In nine of these 51 patients, who had been examined between 1985 and 1992 when the significance of the coarse nodular pattern was still emerging, US-guided fine-needle biopsy for cytologic and histologic analysis was performed in one of the hypoechoic nodules, and there was no evidence of neoplastic cells in any of the specimens examined.

In all four of the other subgroups, the coarse echo pattern was the most common finding although about one-fourth of patients in the PBC and ALC groups had, respectively, normal and bright liver patterns.

At the time of diagnosis, mean serum AFP levels for the subgroups in the study were not significantly different (P = .08); AFP levels in the PBC group were decreased but not statistically different from the level in all other groups (Table 1). The mean AFP levels showed no significant association with the US pattern of the liver parenchyma.

Incidence of HCC during Follow-up
The mean length of follow-up considered for the study population as a whole was 43.9 months ± 29.9, and there were no significant (P = .24) differences between the means of the five subgroups.

During the follow-up period, HCC had been diagnosed in 40 (10.0%) of 402 patients. Solitary tumors were found in 35 cases, and multifocal disease was determined in five. All of the malignant nodules had been depicted on routine US scans, and the final diagnosis of HCC was based on diagnostic serum AFP levels (>200 ng/mL [200 µg/L]) at the time of nodule detection (five cases) and positive cytologic and/or histologic findings at US-guided fine-needle biopsy (31 cases), hepatic angiography (three cases), or contrast-enhanced CT (one case).

Table 3 shows the relationships between the incidence of HCC, the cause of cirrhosis, and the parenchymal US pattern when cirrhosis was diagnosed. The incidence of HCC in the HBV (15 [16%] of 94) and HCV (16 [16%] of 100) groups was significantly higher than that in the HDV (four [4%] of 100), ALC (five [8%] of 63), and PBC (0%) groups (P = .002, {chi}2 test = 17.1).


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  		TABLE 3. Relationship between HCC Development and US Hepatic Parenchymal Pattern in Five Etiologic Subgroups of Patients with Cirrhosis

 
In the HBV, HCV, and ALC groups (but not in the HDV group), the presence of the coarse hypoechoic nodular pattern was associated with a significantly increased risk for HCC. For patients with this pattern, the cumulative risk of HCC ± standard error was 11.5% ± 8.3 for those with HDV-related disease, 100.9% ± 54.8 for those with HBV-related disease, 156.9% ± 88.5 for those with HCV-related disease, and 87.5% ± 73 for those with ALC-related disease. Log-rank analysis of these four curves indicated a significant difference (P = .012) (Fig 5). Percentages higher than 100% for HBV and HCV groups were caused by the relatively low number of cases, which caused the trend to be unequivocally clear.



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  		Figure 5. Graph shows cumulative risks of HCC associated with the coarse nodular US pattern in etiologic subgroups of cirrhosis. In HDV-related disease, the risk is 11.5% ± 8.3 (standard error); in HBV-related disease, 100.9% ± 54.8 (standard error); in HCV-related disease, 156.9% ± 88.5 (standard error); in ALC, 87.5% ± 73 (standard error). A log-rank test of the four curves indicated a significant difference (P = .012).

 
The presence of the coarse echo pattern also represented a risk factor for HCC development in all etiologic groups except the PBC group; none of the patients with PBC developed HCC during the follow-up. During the observation period, the cumulative risk of HCC ± standard error for patients who had coarse echo patterns was as follows: 7.1% ± 5 in the HDV group, 33.6% ± 11.9 in the HBV group, 52.8% ± 20.8 in the HCV group, and 13.8% ± 8.5 in the ALC group. A log-rank test of these four cumulative risks did not indicate a significant difference (P = .98) (Fig 6).



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  		Figure 6. Graph shows cumulative risk of HCC associated with the coarse echo pattern in etiologic subgroups of cirrhosis. In HDV-related disease, the risk is 7.1% ± 5 (standard error); in HBV-related disease, 33.6% ± 11.9 (standard error); in HCV-related disease, 52.8% ± 20.8 (standard error); in ALC-related disease, 13.8% ± 8.5 (standard error). A log-rank test of the four curves did not indicate a significant difference (P = .98).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
The number of new cases of HDV has recently diminished in Italy, and currently observed patients represent cohorts infected years ago (11). HDV superinfection in patients with HBV-related chronic liver disease was previously thought to be a promoting factor for HCC development (12). However, findings in other reports have indicated that it is not associated with earlier development of HCC or a worse prognosis (13).

A meta-analysis of 32 case-control studies (14) revealed that the estimated risk of developing HCC in carriers of the serum hepatitis B surface antigen is 20 times higher than is the risk in seronegative controls, and the risk in HCV carriers is approximately 24 times that of noncarriers. The emerging consensus is that the severity of the liver disease is the primary modulator of HCC risk in both HBV and HCV carriers. Apart from nodular regeneration and cirrhosis, chronic viral hepatitis probably also causes errors in the hepatocyte genome, as well as unregulated growth and repair mechanisms, which over time can result in dysplasia and sometimes in HCC (15).

Our findings confirm those of Kato et al (16), which were published in a 1994 study, that patients with cirrhosis who have HBV- and/or HCV-related disease are at higher risk for HCC than those with non-B and non-C disease; the incidence of HCC among our ALC patients was, in fact, roughly half that of the HBV and HCV patients. In addition, our data indicate that PBC does not seem to represent any risk whatsoever for HCC development. It should perhaps be noted that, while the mean follow-up for this group of patients was more than 3.5 years, only 12 months of follow-up data were analyzed for eight cases.

In clinical practice, early diagnosis represents the major key to successful treatment of HCC, which is far more likely when the tumor is still small. The screening protocol most widely used for this purpose, particularly in Europe and Asia, includes periodic US scanning together with determination of AFP levels, an approach that has proved to be highly cost effective. In a study conducted at the end of the 1980s, Takayasu et al (17) determined that US had a sensitivity of approximately 80% in the detection of HCC nodules smaller than 3 cm in diameter.

At US, small HCCs usually appear as well-circumscribed hypoechoic masses, with a maximum range in diameter of 6–30 mm, although atypical variants are by no means rare. For this reason, a patient with cirrhosis, one who represents a very high risk for HCC, who has solid focal lesions at hepatic US must undergo additional imaging (eg, CT or magnetic resonance imaging, both of which are more costly than US) and/or fine-needle biopsy for histologic and/or cytologic analysis. The lesion should always be considered HCC until it is proved to be otherwise (18).

HCC will, of course, be excluded in a small percentage of cases, and some HCCs will ultimately prove to be benign lesions. Regenerative macronodules, for example, can appear in cirrhotic livers as hypoechoic nodules (19–21) that resemble small HCCs (22), and these benign lesions are present more frequently in livers characterized by the coarse hypoechoic nodular pattern than they are in those with other parenchymal echo patterns (19). The situation is somewhat different when a previously undetected focal liver lesion is discovered in a patient with cirrhosis who has been undergoing US screening for some time. In these cases, HCC is by far the most probable diagnosis, and if the nodule is associated with a serum AFP level of greater than 200 ng/mL (200 µg/L), further investigation is generally considered superfluous (23).

As our findings suggest, the US appearance of the liver parenchyma when cirrhosis is first diagnosed can provide an indication of the actual risk of HCC. Even with the older scanners used during the early years of this study, the patterns we used are easy to identify, as our interreviewer concordance rate suggests. In fact, the 13 cases characterized by discordant opinions showed no correlation with the time of the original examination or the equipment used. As shown in Table 3, regardless of the cause of the disease, none of the patients who had normal or bright parenchymal patterns on the initial scan developed HCC during the follow-up period. These patterns were particularly common in the ALC and PBC groups (Table 2), and in both of these groups, rates of HCC were much lower than they were in the HBV and HCV groups.

Nonetheless, the coarse echo pattern without nodules is the one most commonly encountered in cirrhotic livers in general, and it is by far the most typical of HBV- and/or HCV-related disease (7). Our findings indicate that the coarse nodular pattern can also be found in almost all types of cirrhosis, but cases with this pattern are definitely in the minority (ie, roughly 10% or less) except in HDV-related cirrhosis. In light of the markedly higher prevalence of this echo pattern in our HDV group (51%), it can be considered suggestive of HDV-related cirrhosis.

The reasons for this association are unclear, but the coarse nodular pattern might reasonably be linked to the peculiar characteristics of HDV replication. HDV-related liver disease is characterized by different phases. In the initial active phase of superinfection, HDV replication predominates over that of HBV, which is suppressed, and alanine aminotransferase levels increase markedly (24). Cirrhosis develops within a few years of infection (25), and at this point, the replicative activity of the HDV appears to be a crucial determinant of the speed of progression. The histologic pattern of extensive inflammation and bridging necrosis commonly observed in severe forms of HDV may be the result of a direct cytotoxic effect of HDV on hepatocytes (26). This aggressive destruction might be expected to stimulate equally aggressive attempts at regeneration manifested macroscopically by the coarse nodular pattern.

Findings in several previous studies indicate that this pattern represents a major added risk factor for HCC development in patients with HCV-related cirrhosis (8,9,27) or with chronic hepatitis (8). The link between the coarse nodular pattern and HCC has yet to be fully explained. However, macronodular cirrhosis is more frequently associated with HCC development than is the micronodular form (28–31). Moreover, patients with cirrhosis whose hepatocytes display accelerated DNA synthesis activity are also at higher risk for HCC development (32), and the hypoechoic coarse nodular pattern is associated with a significantly higher liver-cell DNA polymerase-labeling index than are other parenchymal echo patterns (8). Finally, among patients with coarse nodular US patterns, those with larger nodules (ie, nodules with a diameter >5 mm) are more likely to develop HCC than their counterparts with smaller nodules (8,27,33).

Although findings indicate that the coarse nodular pattern increases the risk for HCC in patients with HCV-related liver cirrhosis (9), there is no published evidence of a similar effect in other etiologic forms of cirrhosis. Our findings confirm that this US pattern constitutes a significant added risk in patients with HCV-related cirrhosis, as well as in those whose disease has been caused by HBV or alcohol abuse. In these three groups, in fact, roughly half of the patients with coarse nodular patterns developed HCC during the follow-up, as opposed to less than 20% of those with the coarse echo pattern without nodules and none of those with normal or bright liver patterns (Table 3). In contrast, even though more than half of the patients in our HDV group had the coarse nodular pattern at diagnosis, only two of these developed HCC.

The mechanism underlying the seemingly protective role of HDV is unclear, but it might be related to the ability of the virus to suppress HBV replication. During the acute phase of HDV superinfection, HBV DNA cannot be detected in the serum, and it usually remains undetectable, at least by traditional methods, during the chronic stage (24). The HDV-induced inhibition of HBV replication, still poorly understood, might be the result of cytotoxic effects exerted by HDV, its direct competition for envelope particles, and/or the release of soluble factors. It is unclear whether the reduced risk of carcinogenesis is directly related to common pathways that regulate both HBV and HDV replication or is simply the result of decreased levels of HBV DNA. In any case, the clinical benefit derived from the interaction between these two viruses is in keeping with findings in previous reports of accelerated hepatitis B surface antigen clearance in HDV patients compared with ordinary hepatitis B surface antigen carriers (34) and a lower rate of reinfection in patients with HDV who have undergone orthotopic liver transplantation (35).

In conclusion, our retrospective review of this large series of patients with hepatic cirrhosis shows that the echostructural features of the liver parenchyma at the time of diagnosis can provide valuable information about the patient’s risk for HCC. The coarse nodular pattern can be observed in almost all etiologic forms of cirrhosis. It characterizes fewer than 20% of cases related to HBV and HBC and an even smaller percentage of those associated with alcohol abuse, but in these forms it clearly constitutes an added risk factor for the development of HCC. In contrast, the coarse nodular US pattern characterizes roughly half of all cases of cirrhosis related to combined HBV and HDV infection, but in this setting it does not have the negative prognostic importance in terms of HCC risk that it has in other etiologic forms of cirrhosis. These findings may reflect the peculiarities of HDV replication and the ability of the HDV to suppress replication of the HBV.


   ACKNOWLEDGMENTS
 
The authors thank Marian Kent for editorial assistance and Matteo Palladino, Department of Scientific Photography, Ospedale Casa Sollievo della Sofferenza, Istituto di Ricovero e Cuza a Carattere Scientifico, San Giovanni Rotondo, Italy, and Maria Grazia Latiano for technical assistance.


   FOOTNOTES
 
Abbreviations: AFP = {alpha}-fetoprotein, ALC = alcoholic cirrhosis, HBV = hepatitis B virus, HCC = hepatocellular carcinoma, HCV = hepatitis C virus, HDV = hepatitis D virus, PBC = primary biliary cirrhosis

Author contributions: Guarantors of integrity of entire study, E.C., I.d.S.; study concepts, E.C., I.d.S.; study design, B.P., S.F.; literature research, L.C., G.A.N.; clinical studies, E.C., L.C., G.A.N., I.d.S.; data acquisition, B.P., G.A.N.; data analysis/interpretation, S.F.; statistical analysis, S.F.; manuscript preparation, E.C.; manuscript definition of intellectual content and revision/review, C.d.V.B., A.A.; manuscript editing, E.C., I.d.S.; manuscript final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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Radiology, October 1, 2004; 233(1): 299 - 300.
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